The overall goal of this project is to determine how sickle cell disease may alter the characteristics of the hematopoietic stem cell populations and the way how hematopoiesis responds to the chronic hemolysis. Over the past year we completed the study on "Circulating Cytokines Response and the level of Erythropoiesis in Sickle Cell Anemia" (Am. J of Hematology 60:105-115) and focused our attention on the behavior of circulating LTC-IC ( Long term culture -Initiating cells ) and clonogenic stem cells in SS disease . Our results show that the SS anemia is characterized by the various degree of mobilization of stem and progenitor cells (on average ,approximately 10-fold). The fact that all progenitors examined were found to be increased ( mainly in patients with elevated HbF) showed that the pathological effect of SS disease is not restricted to erythroid lineage only, but affects the entirety of stem cell compartment. Correlation analysis of the circulating LTC-IC and CFC values for individual SS patients confirmed that the changes seen were not compartment specific Additional evidence of a common underlying mechanism was obtained from a horizontal studies performed on a subset of individual SS patients .These studies showed that the numbers of all progenitors fluctuated markedly over time but in correlated fashion . The majority of circulating LTC-IC were found to be quiescent, but were recruited into the cycle more rapidly than thus of normal individuals. The present findings provide evidence that SS anemia is not associated with any signs of exhaustion of circulating stem and progenitors cells. On the contrary, that these cells, in sickle cell anemia circulate in increased numbers and may be particulary suited as a target for gene transfer.